Universal reference book for medicines
Product name: MYCONYL (MYCONYL)

Active substance: fluconazole

Type: Antifungal medication

Manufacturer: CLARIS LIFESCIENCES (India)
Composition, form of production and packaging
Solution for infusion
1 ml

fluconazole 2 mg

100 ml - polyethylene bottles (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

Representative of the class of triazole derivatives.
Has a highly specific effect, inhibiting the activity of cytochrome P450 fungi. Blocking the conversion of lanosterol of fungal cells to ergosterol; increases the permeability of the cell membrane.
Fluconazole, being highly selective for cytochrome P450 fungi, practically does not inhibit these enzymes in the human body (in comparison with itraconazole, clotrimazole, econazole and ketoconazole less inhibits oxidative processes dependent on cytochrome P450 in human liver microsomes).
Does not have anti-androgenic activity.
It is active in opportunistic mycoses, including those caused by Candida spp.
(including generalized forms of candidiasis on the background of immunodepression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp .; with endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including immunosuppression).
PHARMACOKINETICS

After iv introduction fluconazole well penetrates into tissues and body fluids.

Distribution.
The concentration in the plasma is in direct proportion to the dose. The concentration of the active substance in breast milk, articular fluid, saliva, sputum and peritoneal fluid is similar to that in plasma.
In the fluid, epidermis and stratum corneum (selective accumulation), concentrations exceeding serum levels are achieved.

It penetrates well into the cerebrospinal fluid, with fungal meningitis, the concentration in the cerebrospinal fluid is about 85% of that in the plasma.

The 90% equilibrium concentration of fluconazole in plasma (C ss ) is reached by 4-5 days.
The introduction of a "shock" dose (on the first day), which is 2 times higher than the usual daily dose, allows one to achieve a concentration corresponding to 90% C ss by 2 days.
Apparent V d approximates the total fluid content in the body.
The connection with plasma proteins is low -11-12%.
Metabolism and excretion.
T 1/2 - 30 hours. It is an inhibitor of the isoenzyme CYP2C9 in the liver. Excreted mainly by the kidneys (80% - unchanged, 11% - in the form of metabolites). The clearance of fluconazole is proportional to the creatinine clearance. The pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, and there is an inverse relationship between T and creatinine clearance (CK). After hemodialysis, within 3 hours, the concentration of fluconazole in the plasma is reduced by 50%. The pharmacokinetics of fluconazole is similar for intravenous administration and ingestion, which makes it easy to switch from one application to another.
INDICATIONS

- cryptococcosis, including cryptococcal meningitis and infections of other localization (for example, lungs, skin), both in patients with normal immune response, and in patients with various forms of immunodepression (including AIDS patients, organ transplantation);
Supportive therapy for the prevention of recurrence of cryptococcosis in AIDS patients;
- generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis infection, such as peritoneal, endocardial, eye, bronchopulmonary and urinary tract infections, including in patients with malignant tumors in intensive care units, patients receiving cytotoxic or immunosuppressive agents, as well as in patients with other factors predisposing to the development of candidiasis;

- prophylaxis of candidiasis in the presence of a high risk of generalized infection, for example in patients with severe or long-lasting neutropenia;

- Deep endemic mycoses (coccidiomycosis and histoplasmosis) in patients with normal immunity;

- oropharyngeal candidiasis, candidiasis of the esophagus and mucous membranes in children.

DOSING MODE

The solution for infusions is injected / drip at a rate of not more than 200 mg / h.
The daily dose of fluconazole depends on the nature and severity of the fungal infection. When transferred from / to the introduction of the drug in the form intended for oral administration, and vice versa, there is no need to change the daily dose.
The solution for infusion is compatible with 20% dextrose solution, Ringer's solution, Hartmann's solution, 5% dextrose solution and 0.9% potassium chloride solution, 4.2% sodium bicarbonate solution, 0.9% sodium chloride solution.
Infusions can be performed with conventional transfusion kits using one of the above solvents.
Adults.
In cryptococcal meningitis and cryptococcal infections of other sites, on the first day 400 mg of fluconazole are prescribed on average, and then continue treatment at a dose of 200-400 mg once a day. The duration of treatment for cryptococcal infections depends on the clinical efficacy, confirmed by mycological examination; with cryptococcal meningitis, it usually lasts a minimum of 6-8 weeks.
To prevent the recurrence of cryptococcal meningitis in AIDS patients after completion of the full course of primary treatment, fluconazole therapy at a dose of 200 mg / day can be continued for a very long time (transition to an oral form is possible).

With candidemia, disseminated candidiasis and other invasive candidiasis infections, the dose is, on average, 400 mg on the first day, and then at 200 mg per day.
With insufficient clinical efficacy, the dose of fluconazole can be increased to 400 mg / day. The duration of therapy depends on clinical effectiveness.
For the prevention of candidiasis in the presence of a high risk of generalized infection, for example in patients with severe or long-lasting neutropenia, the recommended dose is 400 mg 1 time / day.
Fluconazole is prescribed several days before the expected appearance of neutropenia and after an increase in the number of neutrophils more than 1000 / μl, treatment is continued for another 7 days.
With deep endemic mycoses, it may be necessary to use the drug in a dose of 200-400 mg / day for up to 2 years.
The duration of therapy is determined individually; it is 11 - 24 months with coccidioidomycosis, with histoplasmosis - 3-17 months (transition to an oral form is possible).
Children.
In children, as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be used in a daily dose, which would exceed that of adults, that is, not more than 400 mg per day. The drug is used daily 1 time / day. If it is necessary to carry out long-term therapy, it is possible to switch to the oral form of fluconazole.
In cryptococcal meningitis and cryptococcal infections of other localizations, as well as in generalized candidiasis in children, the recommended dose is 6-12 mg / kg / day, depending on the severity of the disease.
The duration of therapy is 10-12 weeks (before laboratory confirmation of absence of pathogens in CSF).
To prevent the recurrence of cryptococcal meningitis in children with AIDS, after the completion of the full course of primary treatment with fluconazole at a dose of 6 mg / kg / day can continue for a long time.

With oropharyngeal candidiasis in children, the recommended dose is 6 mg / kg / day on the first day, then daily at 3 mg / kg / day, once.
Duration of therapy - for at least 2 weeks.
When candidiasis of mucous membranes in children the recommended dose of fluconazole is 3 mg / kg / day.
On the first day, a shock dose of 6 mg / kg may be prescribed to achieve a more rapid equilibrium equilibrium concentration. The duration of therapy is at least 3 weeks.
When candidiasis of the esophagus in children, fluconazole is administered once in a dose of 3 mg / kg / day.
On the first day, a shock dose of 6 mg / kg / day can be prescribed. Depending on the severity of the disease, the dose can be increased to 6-12 mg / kg / day. The duration of the therapy is at least 3 weeks and 2 weeks after the regression of the symptoms.
For the prevention of fungal infections in children with reduced immunity, in which the risk of infection is associated with neutropenia, resulting from cytotoxic chemotherapy or radiation therapy, fluconazole is administered once in a dose of 3-12 mg / kg / day.
The duration of therapy is until elimination of induced neutropenia.
Use of the drug in children under 4 weeks.
It should be borne in mind that in newborns fluconazole is withdrawn slowly. The first 2 weeks of life the drug is prescribed in the same dose (in mg / kg) as for older children, but at an interval of 72 hours. Children aged 3 and 4 weeks are administered the same dose at intervals of 48 hours.
Aged people.
In the absence of violations of the kidneys should follow the usual dosage regimen.
Patients with impaired renal function.
At QC less than 50 ml / min, the dosage regimen is required.
Fluconazole is excreted mainly with urine in unchanged form.
With a single application, a dose change is not required. In patients with impaired renal function with repeated use of the drug, a shock dose of 50 mg to 400 mg should be initially administered, after which the daily dose (depending on the indications) is determined according to the following table:
Creatinine clearance (mL / min) Percent recommended dose

> 50 100%

?
50 (without dialysis) 50%
Patients on continuous dialysis 100% after each dialysis session

In children with impaired renal function, the daily dose of the drug should be reduced (in the same proportion as in adults), in accordance with the degree of renal insufficiency.

The drug solution contains 0.9% sodium chloride;
in each vial of 100 ml contains 15 mmol Na + (sodium ions) and CL - (chloride ions), therefore, in patients who require a restriction of sodium or liquid intake, the rate of fluid administration must be considered.
SIDE EFFECT

Fluconazole, as a rule, is well tolerated.

Depending on the frequency of occurrence, the following groups of side effects are distinguished: often - more than 1%, infrequently - 0.1-1%, rarely -0.01-0.1%;
very rarely - less than 0.01%.
Allergic reactions: infrequent skin rash, rarely - multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), anaphylactoid reactions (including angioedema, face swelling, hives, itching of the skin).

From the side of the central nervous system: infrequently - headache, dizziness, rarely - convulsions.

On the part of the gastrointestinal tract: infrequently - nausea, diarrhea, flatulence, abdominal pain, taste change, vomiting, rarely - liver dysfunction (jaundice, hyperbilirubinemia, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT) and alkaline phosphatase ), hepatitis, hepatocellular necrosis), including those with a fatal outcome.

On the part of the organs of hematopoiesis: rarely - leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

On the part of the cardiovascular system: rarely - prolongation of the QT interval, very rarely glintening / fluttering of the ventricles.

Other: rarely - a violation of kidney function, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

CONTRAINDICATIONS

Hypersensitivity to the components of the drug, as well as to other antifungal agents - azole derivatives;
simultaneous application of terfenadine (against the background of the continuous use of fluconazole at a dose of 400 mg / day or more) or astemizole; lactation period.
Carefully.
Hepatic insufficiency, the appearance of rash on the background of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, simultaneous use of terfenadine and fluconazole at a dose of less than 400 mg / day, potentially pro-rhythmogenic states in patients with multiple risk factors (organic heart disease, disorders electrolyte balance, simultaneous use of drugs that cause arrhythmias, simultaneous reception with rifabutin and other inducers of cytochrome P450, acetylsalicylic acid), pregnancy.
PREGNANCY AND LACTATION

Avoid the use of fluconazole in pregnancy, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of fluconazole for the mother significantly exceeds the possible risk to the fetus.
Since the concentration of fluconazole in breast milk and in plasma is the same, it is contraindicated to apply the drug during the period of breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER

With caution in the violation of kidney function.
At QC less than 50 ml / min, the dosage regimen is required.
During the treatment, it is necessary to monitor the kidney function.
If there is a violation of the kidneys should stop using the drug.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution: liver failure.

During the treatment it is necessary to monitor the function of the liver.
If a liver function disorder occurs, discontinue use of the drug. In rare cases, the use of fluconazole was accompanied by toxic changes in the liver.
In the case of hepatotoxic effects associated with fluconazole, their development was not dependent on the total daily dose, duration of therapy, sex and age of the patient.
The hepatotoxic effect of fluconazole was usually reversible; signs of it disappeared after discontinuation of therapy. If there are clinical signs of liver damage that may be associated with fluconazole, the drug should be discontinued.
APPLICATION FOR CHILDREN

The application is possible according to the dosing regimen.

APPLICATION IN ELDERLY PATIENTS

In the absence of violations of kidney function in the elderly, the drug should be administered in the usual dosing regimen.

SPECIAL INSTRUCTIONS

Treatment should continue until the appearance of clinical-hematologic remission.
Premature termination of treatment leads to relapse.
Treatment can be started in the absence of seeding results or other laboratory tests, but if appropriate, appropriate correction of antifungal therapy is recommended.

During the treatment, it is necessary to monitor the blood counts (cellular composition, coagulability), kidney and liver function.
It is necessary to monitor the prothrombin index when used simultaneously with indirect anticoagulants - coumarin derivatives. If there is a violation of kidney and liver function, stop using the drug. In rare cases, the use of fluconazole was accompanied by toxic changes in the liver.
In the case of hepatotoxic effects associated with fluconazole, their development was not dependent on the total daily dose, duration of therapy, sex and age of the patient.
The hepatotoxic effect of fluconazole was usually reversible; signs of it disappeared after discontinuation of therapy. If there are clinical signs of liver damage that may be associated with fluconazole, the drug should be discontinued. Patients with AIDS are more likely to develop severe skin reactions with many drugs. In those cases when the rash develops in patients with superficial fungal infection and it is regarded as definitely associated with fluconazole, the drug should be discontinued. When rashes occur in patients with systemic fungal infections, patients should be carefully monitored and when there are bullous changes or erythema multiforme fluconazole must be canceled.
It is recommended to monitor the concentration of cyclosporine in the blood in patients receiving fluconazole, since in patients with kidney transplantation the use of fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine in the plasma.
Care must be taken when fluconazole is used simultaneously with cisapride, rifabutin, or other drugs metabolized by the cytochrome P450 system.
Influence on ability to operate mechanisms and the car.
During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
OVERDOSE

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic, forced diuresis.
Hemodialysis within 3 hours reduces the concentration in the plasma by approximately 50%.
DRUG INTERACTION

Anticoagulants.
Fluconazole increases prothrombin time of indirect anticoagulants - coumarin derivatives (for example, warfarin) by an average of 12%, therefore careful monitoring of prothrombin time is required in patients taking fluconazole and indirect anticoagulants - coumarin derivatives.
Oral hypoglycemic drugs, derivatives of sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide).
When used simultaneously with fluconazole T 1/2oral hypoglycemic drugs, derivatives of sulfonylureas, lengthens, which can lead to the development of hypoglycemia. Periodically monitor the concentration of glucose in the blood and, if necessary, adjust the dose of hypoglycemic drugs.
Hydrochlorothiazide increases the concentration of fluconazole in plasma by 40%, but this does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time.

Phenytoin.
Simultaneous use of fluconazole and phenytoin is accompanied by an increase in the concentration of the latter in a clinically significant degree. Therefore, it is necessary to monitor the concentration of phenytoin and select its dose to provide a therapeutic concentration in the plasma.
Oral contraceptives.
Multiple application of fluconazole (in doses of 50-200 mg) does not affect the effectiveness of combined oral contraceptives.
Rifampicin.
The simultaneous use of fluconazole and rifampicin resulted in a decrease by 25% AUC by 20% and the duration T 1/2 fluconazole. With simultaneous use of rifampicin and fluconazole, it is necessary to take into account the dose of fluconazole.
Cyclosporine. In the treatment of fluconazole is recommended to control the concentration of cyclosporine in the blood.
Theophylline. Fluconazole prolongs the half-life of theophylline, and increases the risk of intoxication (it is necessary dose adjustment).
Terfenadine. The simultaneous use of fluconazole in doses of 400 mg / day or more is contraindicated. Fluconazole treatment at doses less than 400 mg / day in combination with terfenadine must be performed under careful medical supervision.
Cisapride.With simultaneous application of fluconazole and cisapride - unwanted reaction from the heart, including paroxysmal ventricular tachycardia (torsade de pointes).
Rifabutin. Concomitant use of fluconazole and rifabutin may increase the plasma concentrations of the latter. With simultaneous application of fluconazole and rifabutin uveitis cases are described. Patients while receiving rifabutin and fluconazole should be carefully observed.
Tacrolimus. Fluconazole increases plasma concentrations of tacrolimus and therefore, increases the risk of nephrotoxicity.
Zidovudine.In patients receiving the combination of fluconazole and zidovudine observed increase in plasma concentrations of zidovudine, which is caused by a decrease in the conversion of the latter into its main metabolite, so you should expect an increase in the side effects of zidovudine.
Midazolam. Fluconazole increases the plasma concentrations of midazolam and therefore, increases the risk of psychomotor effects (most pronounced when using Fluconazole inside than on / in).
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The preparation is stored in a dry, dark place at a temperature not higher than 30 ° C.
Do not freeze. Keep out of the reach of children.
Shelf life - 3 years.
Do not use after the expiration date.
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